c-Fos is a critical mediator of inflammatory-mediated repression of the apical sodium-dependent bile acid transporter

Gastroenterology. 2006 Aug;131(2):554-67. doi: 10.1053/j.gastro.2006.05.002.


Background & aims: Ileal bile acid malabsorption is present in Crohn's ileitis. The molecular mechanisms of regulation of the apical sodium-dependent bile acid transporter (ASBT) by inflammatory cytokines in vitro and in vivo are investigated.

Methods: Transient transfection studies of the human, mouse, and rat ASBT promoters and Northern analyses were performed in cells treated with the inflammatory cytokines and/or various activator protein-1 constructs. Rat ASBT promoter transgenic, wild-type, and c-fos-null mice were treated with indomethacin to assess the response to acute inflammation of the ileal mucosa.

Results: In Caco-2 cells, ASBT messenger RNA expression was reduced 65% after interleukin-1beta treatment, while c-fos and c-jun were up-regulated 2-fold. Human ASBT promoter activity was enhanced by c-jun and repressed by a dominant negative c-jun, c-fos, or a dominant negative c-fos. Meanwhile, c-fos antisense treatment activated the human ASBT promoter 5-fold and not only abrogated interleukin-1beta-mediated repression but led to a paradoxical increase in ASBT promoter activity. Indomethacin-induced acute ileitis led to repression of ASBT in wild-type mice and in the transgenic rat ASBT promoter reporter, while paradoxical activation of ASBT was seen in c-fos-null mice. Indomethacin-induced ileal injury was greater in the c-fos-null mice compared with the wild-type littermates.

Conclusions: Human, rat, and mouse ASBT is inhibited by inflammatory cytokines via direct interactions of c-fos with the ASBT promoter.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Blotting, Northern
  • Caco-2 Cells / metabolism
  • Caco-2 Cells / pathology
  • Cells, Cultured
  • Gene Expression / drug effects
  • Humans
  • Ileitis / chemically induced
  • Ileitis / metabolism*
  • Ileitis / pathology
  • In Vitro Techniques
  • Indomethacin / toxicity
  • Interleukin-1 / pharmacology
  • Intestinal Mucosa / metabolism*
  • Intestinal Mucosa / pathology
  • Membrane Glycoproteins / metabolism
  • Mice
  • Mice, Knockout
  • Organic Anion Transporters, Sodium-Dependent / genetics
  • Organic Anion Transporters, Sodium-Dependent / metabolism*
  • Proto-Oncogene Proteins c-fos / metabolism*
  • RNA, Messenger / genetics
  • Rats
  • Symporters / genetics
  • Symporters / metabolism*


  • Interleukin-1
  • Membrane Glycoproteins
  • Organic Anion Transporters, Sodium-Dependent
  • Proto-Oncogene Proteins c-fos
  • RNA, Messenger
  • Symporters
  • sodium-bile acid cotransporter
  • Indomethacin